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Mechanisms of resistance to therapies targeting BRCA-mutant cancers

Nature Medicine volume 19, pages 1381–1388 (2013)Cite this article

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Abstract

Synthetic lethality provides a potential mechanistic framework for the therapeutic targeting of genetic and functional deficiencies in cancers and is now being explored widely. The first clinical exemplification of synthetic lethality in cancer has been the exploitation of inhibitors of poly-(ADP-ribose) polymerase (PARP) for the treatment of cancers with defects in the BRCA1 or BRCA2 tumor suppressor proteins, which are involved in the repair of DNA damage. Although this approach has shown promise, multiple potential resistance mechanisms have been identified. In this Perspective, we discuss these mechanisms and their relevance to the development of selective therapies for BRCA-deficient cancers.

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Figure 1: Molecular routes to PARP-inhibitor sensitivity and resistance.
Figure 2: Genetic concepts used in the development of anticancer therapies.
Figure 3: A suggested toolkit for monitoring resistance in the development of PARP inhibitors.

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Acknowledgements

We thank Cancer Research UK, Breakthrough Breast Cancer, the American Association for Cancer Research as part of the Stand Up to Cancer Breast Cancer Dream Team, The Komen Foundation, The Breast Cancer Research Foundation, The Wellcome Trust and the European Union as part of the FP7 DNA Damage Response (DDR) and EUROCAN programmes for funding our work.

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  1. The Breakthrough Breast Cancer Research Centre and Cancer Research UK Gene Function Laboratory, The Institute of Cancer Research, London, UK

    Christopher J Lord & Alan Ashworth

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  1. Christopher J Lord
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Correspondence to Christopher J Lord or Alan Ashworth.

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Competing interests

C.J.L. and A.A. are named inventors on patents describing the use of PARP inhibitors and stand to gain from their development as part of the Institute of Cancer Research “Rewards to Inventors” scheme.

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Lord, C., Ashworth, A. Mechanisms of resistance to therapies targeting BRCA-mutant cancers. Nat Med 19, 1381–1388 (2013). https://doi.org/10.1038/nm.3369

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